Process for manufacturing α,α&#39;-diaminoalcohol

ABSTRACT

A process for the manufacture of the α,α&#39;-diaminoalcohol of formula ##STR1## is via N-protected L-phenylalanine lower alkyl esters, corresponding N-protected α-amino-α&#39;-haloketones, and α-amino-α&#39;-haloalcohols.

This is a division of application Ser. No. 08/718,109, filed Sep. 18, 1996, U.S. Pat. No. 5,684,176 which is a Rule 60 divisional of Ser. No. 08/514,329, filed Aug. 11, 1995, U.S. Pat. No. 5,591,885.

BACKGROUND OF THE INVENTION

1. Field

The present invention is concerned with a novel process and intermediates for the manufacture of an α,α'-diaminoalcohol.

2. Description

The compound 2- 3(S)-amino-2(R)-hydroxy-4-phenylbutyl!-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula ##STR2## is specifically described in Example 1 of European Patent Publication 0432695 and in corresponding U.S. Pat. No. 5,196,438, the contents of which are herein incorporated by reference, and is a valuable intermediate for the manufacture of the pharmacologically active compounds described in these patents. The compound of formula I can be converted as described in Examples 1 and 3 of the identified publications into pharmacologically active compounds suitable for treatment of viral infections, and especially infections caused by HIV and other retroviruses.

SUMMARY OF THE INVENTION

The present invention provides a process for the manufacture of 2- 3(S)-amino-2(R)-hydroxy-4-phenyl-butyl!-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula ##STR3## and includes the novel intermediates generated therein.

The subject process comprises reacting an L-phenylalanine lower alkyl ester with a chloroformic acid ester of the formula ClCOOR¹, wherein R¹ is lower alkyl, benzyl, or phenyl, to produce a diester of formula ##STR4## wherein R is lower alkyl and R¹ is defined as above.

The resulting diester of the formula II is reacted with halogenated methyllithium to produce a halogenated α-aminoketone of formula ##STR5## wherein X is halogen and R¹ is defined as above.

The resulting halogenated α-aminoketone of formula III is then reduced to produce a halogenated α-amino catechol of formula ##STR6## wherein X and R¹ are as defined above.

The resulting halogenated α-aminoalcohol of the formula IV is then cyclized with a base to produce an (S)-1- (S)-oxiran-2-yl!-2-phenyl-ethyl!-carbamic acid ester of formula ##STR7## wherein R¹ is as defined above.

The resulting (S)-1- (S)-oxiran-2-yl!-2-phenyl-ethyl!-carbamic acid ester of formula V is then reacted with N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of formula ##STR8## to produce a methyl (1S,2R)- 1-benzyl-3- (3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinoline-2-yl!-2-hydroxy-propyl!-carbamate of formula ##STR9##

The resulting methyl (1S,2R)- 1-benzyl-3- (3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinoline-2-yl!-2-hydroxy-propyl!-carbamate of formula VII is then treated with a base to produce the 2- 3(S)-amino-2(R)-hydroxy-4-phenyl-butyl!-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention, but are not to be construed as limiting.

The process in accordance with the invention comprises

a) reacting a L-phenylalanine lower-alkyl ester with a chloroformic acid ester of the formula ClCOOR¹, wherein R¹ is lower alkyl, benzyl or phenyl,

b) reacting a resulting diester of the formula ##STR10## wherein R is lower alkyl and R¹ has the above significance, with halogenated methyllithium,

c) reducing a resulting halogenated α-aminoketone of the formula ##STR11## wherein X is halogen and R¹ has the above significance, d) cyclizing a resulting halogenated α-aminoalcohol of the formula ##STR12## wherein X and R¹ have the above significance, with a base, e) reacting a resulting (S)-1- (S)-oxiran-2-yl!-2-phenyl-ethyl!-carbamic acid ester of the formula ##STR13## wherein R¹ has the above significance, with N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula ##STR14## and f) treating the resulting methyl (1S,2R)- 1-benzyl-3- (3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinoline-2-yl!-2-hydroxy-propyl!-carbamate of the formula ##STR15## with a base.

The term "lower alkyl" used above refers to straight-chain or branched saturated hydrocarbon residues with 1-8, preferably 1-4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, pentyl, hexyl, heptyl, octyl, and the like. Halogen denotes bromine, chlorine, fluorine, or iodine.

The diesters of formula II are obtained according to known methods by heating L-phenylalanine with thionyl chloride in a lower alkanol such as methanol, evaporating the lower alkanol and reacting the resulting L-phenylalanine lower alkyl ester with a chloroformic acid ester ClCOOR¹, wherein R¹ signifies lower alkyl, for example, methyl or ethyl, benzyl, or phenyl, in a solvent such as a ketone, for example, methyl ethyl ketone, or an ether, for example, tert.butyl methyl ether, or a hydrocarbon, preferably toluene, in the presence of a base such as a lower alkylamine or an alkali or alkaline earth metal hydroxide, preferably potassium or sodium hydroxide, in the presence of water, at a temperature of 0°-60° C., preferably at 0°-10° C., at pH 4-10, preferably 6-7.

The halomethylation of the resulting diester II is preferably effected using halogenated methyllithium which is generated in situ. The latter is conveniently formed using dihalogenated methane, preferably using bromochloromethane, and a lower alkyl-lithium, preferably butyllithium or hexyllithium, in an ether, preferably tetrahydrofuran, at -20° to -120° C., preferably -80° C.

The halomethylation of the diester II to the halogenated α-aminoketone III can conveniently be carried out by

a) reacting a diester of the formula ##STR16## wherein R is lower-alkyl and R¹ has the above significance, with a lower-alkyl-lithium and an organochlorosilane of the formula ClSi(R²,R³,R⁴), wherein R², R³ and R⁴ are lower alkyl or phenyl, and

b) reacting a silyl-protected compound of formula VIII or IX formed as an intermediate ##STR17## wherein R, R¹, R², R³ and R⁴ have the above significance, in the presence of dihalogenated methane and a lower alkyl-lithium.

It has surprisingly been found that the foregoing protection of the carbamate group present in the diester II by a silyl group with the formation of the compounds of formula VIII or IX above as intermediates leads to a considerable increase in yield. Butyllithium or hexyllithium is preferably used as the lower alkyl-lithium and chlorotrimethylsilane is preferably used as the organochlorosilane ClSi(R²,R³,R⁴). Moreover, an almost complete conversion can be achieved using significantly less lower alkyl-lithium and dihalogenated methane.

The reduction of the halomethyl ketone III is conveniently carried out in a solvent such as toluene, tetrahydrofuran or an alcohol, preferably methanol, ethanol or isopropanol, at a temperature between -30° and 80° C., preferably -15° C. and 50° C., optionally under reduced pressure, using sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, lithium aluminum tri-tert.-butoxyhydride, sodium borohydride, tetra-methylammonium borohydride or, preferably, using an aluminum tri-alkoxide or lithium aluminum tri-alkoxyhydride. The term "alkoxide" embraces straight-chain or branched-chain saturated hydrocarbon oxides with 1-8, preferably 3-4, carbon atoms, namely methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl oxide as well as pentyl, hexyl, heptyl and octyl oxides. The aluminum compounds can have identical or different alkoxide groups. Aluminum tri-isopropoxide and aluminum tri-sec.-butoxide are especially preferred compounds. The reagents lithium aluminum tri-tert.-butoxyhydride, aluminum tri-isopropoxide and aluminum tri-sec.-butoxide gave unexpectedly a high stereoselectivity of 95:5 of the (1S,2S) and (1S,2R) isomeric halohydrins IV, which could be crystallized from the reaction medium in >99% optical purity and with high yield.

The ring closure of the halohydrin of formula IV is conveniently carried out in a solvent such as ethanol or preferably a toluene/water mixture in the presence of a base such as an alkali or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide, at a temperature between 0° and 80° C., preferably 40°-50° C., whereby the epoxide of formula V which is formed need not be purified.

The reaction of the epoxide of formula V with the amide VI is conveniently carried out in a solvent such as a hydrocarbon, for example, toluene, or a lower alkanol, preferably ethanol, while heating to the reflux temperature, preferably at 20°-100° C., especially at 80° C.

The cleavage of the N-protecting group from the compound of formula VII is conveniently effected in a solvent such as water, ethanol or a mixture thereof using a base such as sodium or potassium hydroxide while heating to the reflux temperature, preferably at 20°-100° C., especially at 80°.

The compounds of formulas III and IV in which R¹ signifies methyl (namely formulas IIIa and IVa, respectively), especially

methyl(S)-1-benzyl-3-chloro-2-oxopropyl)carbamate and, respectively,

methyl(1S,2S)-(1-benzyl-3-chloro-2-hydroxypropyl)carbamate as well as the compounds of formulas V and VII in which R¹ signifies methyl (namely formulas Va and VIIa, respectively), namely

methyl (S)-1- (S)-oxiran-2-yl!-2-phenethyl!carbamate and, respectively,

methyl(1S,2R)- 1-benzyl-3- (3S,4aS,8aS)-3-tert-butoxy carbamoyl-octahydro-isoquinolin-2-yl!-2-hydroxypropyl!carbamate,

are novel and as such are encompassed by the present invention. The invention likewise embraces the compounds of formulas I, III and IV, which can be obtained by the process described above, as well as the use of the compounds of formulas III and IV for the manufacture of the compounds of formula I.

The compound of formula VI which is used as the starting material is known and corresponds to that of formula VII in European Patent Publication 0 432 695 and U.S. Pat. No. 5,196,438, the contents of which are herein incorporated by reference.

The following Examples are intended to illustrate the present invention, but are not limiting in any manner.

EXAMPLE 1

160 ml of thionyl chloride were added dropwise to 800 ml of methanol at 0° C. Subsequently, the mixture was treated with 330.4 g of L-phenylalanine and heated to 45° C. for 2.5 hours. The resulting solution was concentrated completely and the residue was taken up in 1.6 1 of water and treated at0° C. with 185 ml of methyl chloroformate while holding the pH between 6-7 with 40% sodium hydroxide solution. The solution was extracted with toluene, the extracts, after washing with water, were concentrated and the residue was dried at 45° C./0.1 mbar, there being obtained 474.6 g (100%) of pure methyl(S)-2-methoxycarbonylamino-3-phenyl-propionate. IR (KBr): 3338 m (NH), 1726 s br. (C═O), 1531 s (amide II).

EXAMPLE 2

41.7 ml of a 2.6 molar solution of hexyllithium in hexane were added dropwise at -80° C. to a solution of 9.50 g of methyl(S)-2-methoxycarbonylamino-3-phenyl-propionate and 3.22 ml of bromochloromethane in 60 ml of tetrahydrofuran. Subsequently, a further 2.14 ml of bromochloromethane were added and the mixture was again treated with 23 ml of hexyllithium solution, a further 1.54 ml of bromochloromethane were added and the mixture was again treated with 7.7 ml of hexyllithium solution. The solution was treated at -80° C. with 15 ml of 20% methanolic hydrochloric acid, warmed to 22° and diluted with 100 ml of water and 40 ml of tetrahydrofuran. The phases were separated, the organic phase was washed with saturated sodium chloride solution, dried and concentrated. The residue was recrystallized from 40 ml of ethyl acetate and 160 ml of hexane and the crystallizate was dried, there being obtained 3.83 g (37%) of pure methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate, m.p. 121°-122° C. IR (KBr): 3336 s (NH), 1737 s and 1686 s (C═O), 1535 s (amide II).

EXAMPLE 3

15.4 ml of a 2.6 molar solution of hexyllithium in hexane were added dropwise at -80° C. to a solution of 9.50 g of methyl(S)-2-methoxycarbonylamino-3-phenyl-propionate in 60 ml of tetrahydrofuran. Subsequently, the mixture was treated with 5.60 ml of chlorotrimethylsilane. The resulting suspension was stirred and treated with 3.22 ml of bromochloromethane. Subsequently, 18.4 ml of hexyllithium solution were added. The solution was treated at -80° C. with 11 ml of 20% methanolic hydrochloric acid, warmed to 22° and diluted with 100 ml of water and 40 ml of tetrahydrofuran. The phases were separated and the organic phase was washed with saturated sodium chloride solution, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane and the crystallizate was dried, there being obtained 7.20 g (70%) of pure methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate, m.p. 122°-123° C. IR (KBr): 3336 s (NH), 1737 s and 1686 s (C═O), 1535 s (amide II).

EXAMPLE 4

A) 33.06 g of lithium aluminum tri-tert.-butoxyhydride were added portionwise at -15° C. to a suspension of 25.57 g of methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate in 280 ml of ethanol and the mixture was subsequently hydrolyzed at 0° C. with 140 ml of 3N hydrochloric acid and 170 ml of water. The suspension was concentrated to 370 ml, filtered and the residue was washed with water/ethanol (4:1) and dried, there being obtained 23.27 g (90%) of isomerically-pure methyl(1S,2S)-(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, m.p. 163°-164.5° C. IR (KBr): 3323 s, br. (NH, OH), 1689 (C═O), 1546 s (amide II).

B) 25.57 g of methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate were added portionwise at 22° C. to a suspension of 21.44 g of aluminum isopropoxide in 260 ml of isopropanol. The suspension was stirred at 50° C./400 mbar for 2 hours, hydrolyzed at 0° C. with 100 ml of 3N hydrochloric acid, subsequently concentrated to a volume of 125 ml, diluted with 125 ml of water, cooled to 0° C. and filtered. The residue was washed with water/isopropanol (4:1) and dried, there being obtained 13.01 g (89%) of isomerically-pure methyl(1S,2S)-(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, m.p. 162°-163.5° C. IR (KBr): 3323 s, br. (NH, OH), 1689(C═O), 1546 s (amide II).

EXAMPLE 5

3.75 g of sodium borohydride were added portionwise at -15° C. to a suspension of 46.03 g of methyl(S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate in 275 ml of methanol. The mixture was stirred for 1.5 hours, diluted with 21 ml of acetic acid and 460 ml of water, stirred at -15° C. for 1 hour and filtered. The residue was washed with water, recrystallized from 430 ml of isopropanol and the crystallizate was dried, there being obtained 28.68 g (62%) of a 98:2 mixture of the (1S,2S):(1S,2R)-isomers of methyl(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, m.p. 161.5°-162.5° C. IR (KBr): 3323 s, br. (NH, OH), 1689 s (C═O), 1546 s (amide II).

EXAMPLE 6

A mixture of 28.35 g of methyl(1S,2S)-(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, 8.8 g of sodium hydroxide, 110 ml of toluene and 110 ml of water was stirred at 40° C. and the organic phase was then washed with water and concentrated. The residual methyl (S)-1- (S)-oxiran-2-yl!-2-phenyl-ethyl!-carbamate was taken up in 130 ml of ethanol, treated with 26.22 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and heated at reflux for 5.3 hours. The suspension was diluted with 80 ml of water, cooled to 22° and filtered, and the residue was washed with a 1:1 mixture of ethanol/water and dried, there being obtained 46.30 g (92%) of methyl(1S,2R)- 1-benzyl-3- (3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl!-2-hydroxy-propyl!-carbamate, m.p. 194°-195° C. IR (KBr): 3411 m and 3317 m (NH, OH), 1715 s and 1659 s (C═O), 1548 s (amide II).

EXAMPLE 7

A suspension of 41.37 g of methyl(1S,2R)- 1-benzyl-3- (3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl!-2-hydroxy-propyl!-carbamate and 23.0 g of sodium hydroxide in 90 ml of ethanol and 90 ml of water was heated at reflux for 3.5 hours, diluted with 45 ml of water and cooled to 22°, and the separated solid was filtered off, washed with a 1:4 mixture of ethanol/water and dried, there being obtained 35.35 g (98%) of pure 2- 3(S)-amino-2(R)-hydroxy-4-phenyl-butyl!-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, m.p. 173°-175° C. IR (KBr): 3435 m, br. (NH, OH), 1665 s (C═O), 1562 m (amide II).

Upon reading the present specification, various alternative embodiments will become obvious to the skilled artisan. These variations are to be considered within the scope and spirit of the present invention which is only to be limited by the claims which follow and their reasonable equivalents. 

What is claimed is:
 1. A process for the manufacture of 2- 3(S)-amino-2(R)-hydroxy-4-phenyl-butyl!-N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of the formula ##STR18## which process comprises: a) reacting an L-phenylalanine lower alkyl ester with a chloroformic acid ester of the formula ClCOOR¹, wherein R¹ is lower alkyl, benzyl, or phenyl, to produce a diester of formula ##STR19## wherein R is lower alkyl and R¹ is defined as above; b) reacting the resulting diester of the formula II with halogenated methyllithium to produce a halogenated α-aminoketone of formula ##STR20## wherein X is halogen and R¹ is defined as above; c) reducing the resulting halogenated α-aminoketone of formula III to produce a halogenated α-amino catechol of formula ##STR21## wherein X and R¹ are as defined above; d) cyclizing a resulting halogenated α-aminoalcohol of the formula IV with a base to produce an (S)-1- (S)-oxiran-2-yl!-2-phenyl-ethyl!-carbamic acid ester of formula ##STR22## wherein R¹ is as defined above; e) reacting the resulting (S)-1- (S)-oxiran-2-yl!-2-phenyl-ethyl!-carbamic acid ester of formula V with N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of formula ##STR23## to produce a methyl(1S,2R)- 1-benzyl-3- (3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinoline-2-yl!-2-hydroxy-propyl!-carbamate of formula ##STR24## f) treating the resulting methyl(1S,2R)- 1-benzyl-3- (3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinoline-2-yl!-2-hydroxy-propyl!-carbamate of formula VII with a base to produce the 2- 3(S)-amino-2(R)-hydroxy-4-phenyl-butyl!-N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide of formula I.
 2. The process of claim 1, wherein the reacting of step (a) is performed in a solvent.
 3. The process of claim 2, wherein the reacting of step (a) is performed in the presence of a solvent selected from the group consisting of ketones, esters, and hydrocarbons.
 4. The process of claim 3, wherein the reacting of step (a) is in the presence of a solvent selected from the group consisting of methyl ethyl ketone, tert-butyl ether, and toluene.
 5. The process of claim 1, wherein the reacting of step (a) is performed in the presence of a base.
 6. The process of claim 5, wherein the reacting of step (a) is in the presence of a base selected from the group consisting of lower alkylamines, alkali earth metal hydroxides, and alkaline earth metal hydroxides.
 7. The process of claim 6, wherein the reacting of step (a) is in the presence of a base selected from the group consisting of potassium hydroxide and sodium hydroxide.
 8. The process of claim 1, wherein the reacting of step (a) is at a temperature of from 0° C. to 60° C.
 9. The process of claim 8, wherein the reacting of step (a) is at a temperature of from 0° C. to 10° C.
 10. The process of claim 1, wherein the reacting of step (a) is at a pH of 4 to
 10. 11. The process of claim 10, wherein the reacting of step (a) is at a pH of 6 to
 7. 12. The process of claim 1, wherein the reacting of step (b) further comprises generating the halogenated methyllithium by reacting a dihalogenated methane with a lower alkyl-lithium.
 13. The process of claim 12, wherein the dihalogenated methane is bromochloromethane and the lower alkyl-lithium is butyllithium or hexyllithium.
 14. The process of claim 1, wherein the reacting of step (b) is performed in the presence of an ether.
 15. The process of claim 14, wherein the ether is tetrahydrofuran.
 16. The process of claim 1, wherein the reacting of step (b) is at a temperature of from -20° C. to -120° C.
 17. The process of claim 16, wherein the reacting of step (b) is at a temperature of -80° C.
 18. The process of claim 1, wherein the reducing of step (c) is performed in the presence of a solvent.
 19. The process of claim 18, wherein the solvent is toluene, tetrahydrofuran, or alcohol.
 20. The process of claim 19, wherein the solvent is an alcohol selected from the group consisting of methanol, ethanol, and isopropanol.
 21. The process of claim 1, wherein the reducing of step (c) is at a temperature of from -15° C to 50° C.
 22. The process of claim 1, wherein the reducing of step (c) comprises reacting the compound of formula IV with compound selected from the group consisting of sodium bis(2-methoxy-ethoxy)aluminum hydride, lithium aluminum hydride, lithium aluminum hydride, lithium aluminum tri-tert-butoxyhydride, sodium borohydride, tetra-methylammonium borohydride, aluminum tri-alkoxide, and lithium aluminum tri-alkoxy hydride.
 23. The process of claim 1, wherein the cyclizing of step (d) is performed in the presence of a solvent.
 24. The process of claim 23, wherein the cyclizing of step (d) is in the presence of a solvent which is a toluene/water mixture.
 25. The process of claim 1, wherein the cyclizing of step (d) is in the presence of a base.
 26. The process of claim 25, wherein the cyclizing of step (d) is in the presence of a base selected from the group consisting of alkali metal hydroxide and alkaline earth metal hydroxide.
 27. The process of claim 26, wherein the cyclizing of step (d) is in the presence of sodium hydroxide or potassium hydroxide.
 28. The process of claim 1, wherein the cyclizing of step (d) is at a temperature of from 0° C. to 80° C.
 29. The process of claim 28, wherein the cyclizing of step (d) is at a temperature of from 40° C. to 50° C.
 30. The process of claim 1, wherein the reacting of step (e) is performed in a solvent.
 31. The process of claim 30, wherein the reacting of step (e) is in the presence of a solvent selected from the group consisting of toluene and lower alkanol.
 32. The process of claim 31, wherein the reacting of step (e) is in the presence of a lower alkanol which is ethanol.
 33. The process of claim 1, wherein the reacting of step (e) is at a temperature of from 20° C. to 100° C.
 34. The process of claim 33, wherein the reacting of step (e) is at a temperature of 80° C.
 35. The process of claim 1, wherein the treating of step (f) is performed in a solvent.
 36. The process of claim 35, wherein the treating of step (f) is in the presence of a solvent selected from the group consisting of water, ethanol, and mixtures of water and ethanol.
 37. The process of claim 1, wherein the treating of step (f) is performed using a base selected from the group consisting of sodium hydroxide and potassium hydroxide. 